WO1996024353A1 - Procede de traitement ou de prevention de troubles psychiatriques - Google Patents

Procede de traitement ou de prevention de troubles psychiatriques Download PDF

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Publication number
WO1996024353A1
WO1996024353A1 PCT/US1996/001737 US9601737W WO9624353A1 WO 1996024353 A1 WO1996024353 A1 WO 1996024353A1 US 9601737 W US9601737 W US 9601737W WO 9624353 A1 WO9624353 A1 WO 9624353A1
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disorder
compound
mammal
serotonin
activity
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PCT/US1996/001737
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English (en)
Inventor
Kirk W. Johnson
Lee A. Phebus
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Eli Lilly And Company
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Priority to AU49187/96A priority Critical patent/AU4918796A/en
Publication of WO1996024353A1 publication Critical patent/WO1996024353A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system provides another example of a peripheral network that is very sensitive to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists.
  • receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophhrenia, autism, neurodegenerative disorders , such as Alzheimer ' s disease , Parkinsonism, and Huntington ' s chorea , and cancer chemotherapy- induced vomiting .
  • M . D . Gershon et al . , THE PERIPHERAL ACTIONS OF 5 -HYDROXYTRYPTAMINE , 246 ( 1989 ) ; P . R . Saxena , et al . , Journal of Cardiovascular Pharmacolocry , 15: Supplement 7 ( 1990 ) .
  • Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. It is now recognized that multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple,
  • serotonin receptors structurally distinct serotonin receptors has provided the possibility that subtype-selective pharmacologic agents can be produced. The development of such compounds could result in new and increasingly selective therapeutic agents with fewer side effects, since activation of individual receptor subtypes may function to affect specific actions of the different parts of the central and/or peripheral serotonergic systems.
  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970 's.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • NK-1 The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
  • Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the
  • Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
  • Tachykinins play a major role in mediating the sensation and transmission of pain or nociception
  • receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
  • tachykinin receptor antagonists are found in European
  • the present invention provides methods for treating persons afflicted with, or with a heightened risk of contracting, one or more disorders selected from the group consisting of panic disorder, panic attack, depression, anxiety, bulimia nervosa, obsessive-compulsive disorder, premenstrual dysphoric disorder, substance abuse, substance dependence, agoraphobia, post-traumatic stress disorder, dementia of Alzheimer's type, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorder, intermittent explosive disorder, borderline personality disorder, chronic fatigue syndrome, premature ejaculation, and depression and
  • This invention further provides methods for the treatment or prevention of a psychiatric disorder in a mammal which comprise the sequential administration to a mammal in need thereof a composition having serotonin agonist activity (or selective serotonin reuptake inhibitor activity) followed by the administration of a composition having tachykinin receptor antagonist activity.
  • This invention also provides methods for the treatment or prevention of a psychiatric disorder in a mammal which comprise the sequential administration to a mammal in need thereof a composition having tachykinin receptor antagonist activity followed by the administration of a composition having serotonin agonist activity (or selective serotonin reuptake inhibitor activity).
  • serotonin binding receptors have been identified. These receptors are generally grouped into seven classes on the basis of their structure and the pharmacology of the receptor as determined by the binding efficiency and drug-related characteristics of numerous serotonin receptor-binding compounds . In some of the groups several subtypes have been identified. [For a relatively recent review of 5-hydroxytryptamine receptors, see, E. Zifa and G. Fillion, Pharamcolo ⁇ ical Reviews, 44:401-458 (1992); D. Hoyer, et al., Pharamcological
  • Table I infra, lists the seven classes of serotonin receptors as well as several known subtypes. This table also provides the physiological distribution of these receptors as well as biological responses mediated by the receptor class or subtype, if any such response is known. This table is derived from D.
  • the 5-HT 1 family includes subtypes which can be grouped together based on the absence of introns in the cloned genes, a common G-coupled protein transduction system (inhibition of adenylate cyclase), and similar operational characteristics.
  • inhibitory receptors includes subtypes A, B, D, E, and F.
  • the 5-HT 1 G protein-linked receptors general inhibit the production of cyclic adenosine monophosphate (cAMP) , while the 5-HT 2 G protein linked receptors stimulate cAMP.
  • cAMP cyclic adenosine monophosphate
  • the 5-HT 1A receptor was the first cloned human serotonin receptor. Activated 5-HT 1A receptors expressed in
  • HeLa cells inhibit forskolin-stimulated adenylate cyclase activity.
  • the 5-HT 1D receptor was originally identified in bovine brain membrane by Heuring and Peroutka. R.E. Heuring and S.J. Peroutka, Journal of Neuroscience, 7:894-903 (1987).
  • the 5-HT 1D receptors are the most common 5-HT receptor subtype in the human brain and may be identical to the 5-HT 1-like receptor in the cranial vasculature. S.D. Silberstein, Headache, 34:408-417 (1994). Sumatriptan and the ergot alkaloids have high affinity for both the human 5-HT 1D and the 5-HT 1B receptors. Id.
  • the 5-HT 1F subtype of receptor has low affinity for 5-carboxamidotryptamine (5-CT) unlike the other 5-HT receptors, except for the 5-HTIE subtype. Unlike the
  • 5-HT 1E receptors however, the 5-HT 1F receptors do show affinity for sumatriptan.
  • the biological efficacy of a compound believed to be effective as a serotonin agonist may be confirmed by first employing an initial screening assay which rapidly and accurately measures the binding of the test compound to one or more serotonin receptors. Once the binding of the test compound to one or more serotonin receptors is confirmed by first employing an initial screening assay which rapidly and accurately measures the binding of the test compound to one or more serotonin receptors. Once the binding of the test compound to one or more serotonin receptors is
  • the ability of a compound to bind to a serotonin receptor was measured using standard procedures. For example, the ability of a compound to bind to the 5-HT 1F receptor substype was performed essentially as described in N. Adham, et al., Proceedings of the National Academy of Sciences (USA), 90:408-412 (1993).
  • the cloned 5-HT 1F receptor was expressed in stably transfected LM(tk-) cells.
  • Membrane preparations were made by growing these transfected cell lines to confluency. The cells were washed twice with phosphate-buffered saline, scraped into 5 ml of ice-cold phosphate-buffered saline, and centrifuged at 200 ⁇ g for about five minutes at 4°C. The pellet was resuspended in 2.5 ml of cold Tris buffer (20 mM Tris-HCl, pH 7.4 at 23°C, 5 mM EDTA) and homogenized. The lysate was centrifuged at
  • Radioligand binding studies were performed using [ 3 H]5-HT (20-30 Ci/mmol). Competition experiments were done by using various concentrations of drug and 4.5-5.5 nM [ 3 H]5-HT. Nonspecific binding was defined by 10 ⁇ M 5-HT. Binding data were analyzed by nonlinear-regression analysis. IC 50 values were converted to K i values using the Cheng-Prusoff equation.
  • binding affinities of compounds for various serotonin receptors may be determined essentially as described above except that different cloned receptors are employed in place of the 5-HT 1F receptor clone employed therein.
  • Adenylate cyclase activity was determined in initial experiments in LM(tk-) cells, using standard techniques. See, e.g., N. Adham, et al., supra.; R.L.
  • Intracellular levels of cAMP were measured using the clonally derived cell line described above. Cells were preincubated for about 20 minutes at 37°C in 5% carbon dioxide, in Dulbecco's modified Eagle's medium containing
  • Varying concentrations of the test compounds were added to ths medium to determine inhibition of forskolin-stimulated adenylate cyclase.
  • Some compounds that bind serotonin receptors show no receptor selectively, i.e. they bind different receptor subtypes with comparable affinity.
  • One example of such a non-selective serotonin receptor binding compound is dihydroergotamine, a compound having the structure and the chemical name, 9 ,10-dihydro-12'-hydroxy-2'-methyl-5'-(phenylmethyl)ergotaman-3',6',18'-trione. This compound is commercially available [as the mesylate salt] or may be prepared as described in Stoll and Hofmann, Helv. Chimica Acta, 26:2070 (1943).
  • a compound having a high affinity for one (or a few) receptor subtype and low affinity for other receptor subtypes using studies analogous to the binding assays supra, is considered to be subtype-selective.
  • 311C90 is believed capable of crossing the blood-brain barrier. Scrip, September 7, 1994.
  • Especially preferred serotonin agonists employed in the methods of this invention are those compounds with a high affinity for the 5-HT 1F subtype of receptor.
  • One such class of compounds is typified by the compound
  • dimethylformamide were added 2.65 g (0.025 mole) sodium carbonate followed by 1.87 g (9.2 mmol) 1-methyl-4-(2-methanesulfonyloxyethyl)-1H-pyrazole. The resulting mixture was heated at 100°C for 18 hours under nitrogen. The dimethylformamide was distilled under reduced pressure and the resulting residue was partitioned between water and dichloromethane. The dichloromethane phase was separated, washed sequentially with water and saturated aqueous sodium chloride solution and then dried over sodium sulfate to give 4.0 g of a brown oil. The brown oil was
  • the starting materials described herein are either commercially available or may be synthesized from commercially available materials using known methods.
  • this invention also encompasses methods for the treatment or prevention of a psychiatric disorder in a mammal which comprise administering to a mammal in need thereof an effective amount of a composition having both tachykinin receptor antagonist activity and selective serotonin reuptake inhibition activity.
  • This invention further provides methods for the treatment or prevention of a psychiatric disorder in a mammal which comprise the sequential administration to a mammal in need thereof a composition having selective serotonin reuptake inhibition activity followed by the administration of a composition having tachykinin receptor antagonist activity.
  • This invention also provides methods for the treatment or prevention of a psychiatric disorder in a mammal which comprise the sequential administration to a mammal in need thereof a composition having tachykinin receptor antagonist activity followed by the administration of a composition having selective serotonin reuptake inhibition activity.
  • the selective serotonin reuptake inhibitors are a series of compounds which selectively inhibit the serotonin transporter on membranes of serotonin neurons. These uptake inhibitors increase the
  • Inhibitors of serotonin uptake increase serotonin action on postsynaptic receptors on target neuron and increase serotonergic neurotransmission, resulting in functional cnosequences that are mostly subtle, i.e., not detectable by gross observation, but are detectable by various specific techniques.
  • serotonin uptake inhibitors reduce aggressive behavior, decrease food uptake, decrease alcohol drinking in reats, decrease rapid-eye-movememt sleep, potentiate morphine analgesia, and the like.
  • Serotonin uptake inhibitors are used clinically in the treatment of mental depression, bulimia, and obsessive-compulsinve disorder. They are also reported to be effective as appetite suppressant drugs in the treatment of obesity, in borderline personality disorder, trichotillomania, panic disorder, and attention deficit hyperactivity disorder. See, e.g., R.W. Fuller, Advances in Biosciences, 85:255-270 (1992).
  • serotonin uptake inhibitors have been reported to have therapeutic benefit in premenstrual syndrome, diabetic neuropathy, certain non-cognitive symptoms of Alzheimer's Disease, chronic pain, and in postanoxic intention myoclonus. Id.
  • One such compound is fluoxetine, a compound having the structure
  • Another selective serotonin reuptake inhibitor which may be employed in the methods of the present invention is citalopram, a compound having the structure
  • This compound may be prepared as described in United States
  • Patent 4,136,193 the entire contents of which are herein incorporated by reference.
  • Another compound belonging to this class of therapeutics is femoxetine, a compound having the structure
  • indalpine a compound having the structure
  • Another such compound is paroxetine, a compound having the structure
  • Sertraline is another SSRI which may be employed in the methods of the present invention.
  • This compound having the chemical name (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, has the following structure.
  • Sertraline may be prepared as described in United States Patent 4,536,518, the entire contents of which are herein incorporated by reference.
  • An additional SSRI which may be employed in the methods of the present invention is zimeldine, a compound of the structure
  • tachykinin receptor antagonists have been described.
  • Patent Cooperation Treaty publication WO 94/01402 published January 20, 1994, describes a series of compounds best typified by the following compound.
  • Patent Cooperation Treaty publication WO 94/07843 describes a series of cyclohexylamine derivatives typified by the following compound
  • Another group of compounds useful as tachykinin receptor antagonists is typified by the following compound.
  • a most preferred class of tachykinin receptor antagonists are those compounds of the following structure
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, methoxy, chloro, and trifluoromethyl, with the proviso that no more than one of R 1 and R 2 can be hydrogen; and Y is
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • the synthesis of these compounds is described in co-pending United States Patent Application Serial Number 08/153,847, filed November 17, 1993. The syntheses of two typical compounds from this class are detailed infra.
  • Chlorotrimethylsilane (70.0 ml, 0.527 mol) was added at a moderate rate to a stirred slurry of D- tryptophan (100.0 g, 0.490 mol) in anhydrous methylene chloride (800 ml) under a nitrogen atmosphere. This mixture was continuously stirred for 4.25 hours.
  • Triethylamine 147.0 ml, 1.055 mol was added, followed by the addition of a solution of triphenylmethyl chloride (147.0 g, 0.552 mol) in methylene chloride (400 ml) using an addition funnel. The mixture was stirred at room temperature, under a nitrogen atmosphere for at least 20 hours. The reaction was quenched by the addition of methanol (500 ml) .
  • the solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. An aqueous work- up involving a 5% citric acid solution (2X) and brine (2X) was then performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The solid was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization.
  • RED-AL ® ' [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3-(1H-indol-3-yl)-N- (2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra . in anhydrous
  • the title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-1-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15°C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50°C.
  • the title compound was prepared by first cooling 2-((4-cyclohexyl)piperazin-1-yl)acetic acid potassium salt to a temperature between -8°C and -15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.
  • the reaction was quenched by the addition of 5 volumes of water.
  • the organic layer was washed once with a saturated sodium bicarbonate solution.
  • the organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent.
  • To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol.
  • the methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.
  • the final volume of isopropyl alcohol was then concentrated to three volumes by vacuum.
  • the reaction mixture was cooled to 20°C to 25°C and the product was allowed to crystallize for at least one hour.
  • the desired product was then recovered by filtration and washed with sufficient isopropyl alcohol to give a colorless filtrate.
  • the crystal cake was then dried under vacuum at 50°C.
  • Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 ⁇ 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous
  • This reaction mixture was stirred at about -10°C for about 1.5 hours at which time the (R)-2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride/methylene chloride mixture prepared supra was slowly added to the 2-(4-(piperidin-1-yl)piperidin-1-yl)acetic acid potassium salt/isobutylchloroformate/methylene chloride solution. The resulting mixture was then stirred for about 1 hour at a temperature between -15°C and -8°C.
  • reaction mixture was removed from the ice bath and allowed to warm to 15-20°C and the reaction was quenched by the addition of 200 ml of water.
  • the pH of the solution was adjusted to 2.3-2.7 by the additon of 1N sulfuric acid.
  • the layers were separated and the aqueous layer was washed with 100 ml of methylene chloride.
  • the organic and aqueous fractions were separated.
  • the aqueous fraction was washed with methylene chloride and the methylene chloride was added to the organic fraction.
  • the organic fraction was then washed with a mixture of
  • reaction mixture was then cooled to -35°C and solid (R)-2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]propane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20°C.
  • the reaction mixture was stirred for about one hour with the temperature being maintained between -37°C and -20°C.
  • the reaction was quenched by the addition of deionized water (7.5 L).
  • the reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium hydroxide.
  • the aqueous fraction was removed and retained. Additional deionized water (3.75 L) was added to the organic fraction as was sufficient 5 N sodium hydroxide to re-adjust the pH to 12.8-13.2.
  • the resulting mixture is then cooled to 0°C, stirred for about ten minutes, and then permitted to warm to room temperature.
  • the progress of the reaction was monitored by chromatography. High performance liquid chromatography showed 99% conversion of the reactants after ninety minutes.
  • the reaction mixture was partitioned between ethyl acetate (375 ml) and a saturated sodium bicarbonate solution (375 ml).
  • the 'aqueous layer was back extracted with 375 ml of ethyl acetate.
  • the organic fractions were combined, washed with water (3 ⁇ 375 ml), and then dried over magnesium sulfate.
  • Potassium hydroxide is then added to the aqueous fraction from above and this resulting basified solution is extracted with ethyl acetate. This organic fraction is then dried over magnesium sulfate.
  • the mixed anhydride process can be performed at temperatures below 0°C.
  • the oxalate can be isolated from ethyl acetate as well as from other solvents, probably including acetone, acetonitrile, and t-butyl methyl ether.
  • the use of oxalic acid is, however, very important for the precipitation as a large number of acids do not give a precipitate.
  • acids attempted, but found not satisfactory for the processes of the present invention are citric, anhydrous hydrochloric, tartaric, mandelic, trifluoroacetic, p-nitrobenzoic, phenoxyacetic, maleic, fumaric, glutaric, adipic, methanesulfonic, p-toluenesulfonic, pamoic, trans-1,2-cyclohexane dicarboxylic, succinic, phthalic, trans-1,2-diaminocyclohexane-N,N,N',N'-naphthalenedisulfonic, and 5-sulfosalicylic acids. Only oxalic acid and 1,5-naphthalene disulfonic acid reproducibly produced a solid.
  • Enough water was added to bring the water concentration to eleven percent (by weight) and the resulting mixture was heated to 55°C.
  • Enough concentrated hydrochloric acid was added to lower the pH to 2.0 and the reaction mixture was then permitted to cool to 37°C over 45 minutes .
  • the product solution was seeded and permitted to stir for 10-30 minutes.
  • the product solution was cooled to 19°C over two hours and acetone (11.8 equivalent volumes) was added over three hours, after which time the reaction mixture was stirred for one to three hours, maintaining the temperature at 19°C.
  • the product solution was filtered and the residue was washed with 10.2 equivalents (by volume) of acetone. The residue was then dried in a vacuum oven at 42°C to give the desired title product. Yield 2.407 grams (80.7%).
  • a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e.g., J. Jukic, et al., Life Sciences. 49:1463-1469 (1991); N. Kucharczyk, et al.,
  • Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al., Journal of Immunology, 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 ⁇ 10 6 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125 I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4°C.
  • the IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g., Annals of the New York Academy of Science, 190: 221-234 (1972); Nature (London), 251:443-444 (1974); Proceedings of the National Academy of Sciences (USA), 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 ⁇ g/ml gentamicin sulfate and 10% fetal calf serum.
  • reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1%
  • NK-2 Receptor Binding Assay The CHO-hNK-2R cells, a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm 2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N.P.
  • the dissociated cells were pooled and centrifuged at 1,000 RPM for 10 minutes in a clinical centrifuge.
  • Membranes were prepared by homogenization of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by
  • concentration of this preparation was 2 mg/ml.
  • DMSO dimethylsulfoxide
  • IC 50 IC 50 determinations.
  • the order of additions for incubation was 190 or 195 ⁇ l assay buffer, 200 ⁇ l homogenate, 10 or 5 ⁇ l sample in DMSO, 100 ⁇ l radioactive ligand.
  • the samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 ⁇ 75 mm polystyrene tubes and counted in a gamma counter.
  • compositions employed in the method of the present invention is a compositions employed in the method of the present invention.
  • the responding of rats or pigeons is maintained by a multiple schedule of food presentation.
  • responding produces food pellet presentation only.
  • responding produces both food pellet presentation and is also punished by presentation of a brief electric shock.
  • Each component of the multiple schedule is approximately 4 minutes in duration, and the shock duration is approximately 0.3 seconds.
  • the shock intensity is adjusted for each individual animal so that the rate of punished responding is approximately 15 to 30% of the rate in the unpunished component of the multiple schedule.
  • Sessions are conducted each weekday and are approximately 60 min in duration.
  • Vehicle or a dose of composition are administered 30 min to 6 hours before the start of the test session by the subcutaneous or oral route.
  • Composition effects for each dose for each animal are calculated as a percent of the vehicle control data for that animal. The data are expressed as the mean ⁇ the standard error of the mean.
  • compositions The antianxiety activity of the compositions is established by demonstrating that the compositions are effective in the monkey taming model. Plotnikoff, Res.
  • the present study is designed to measure the pole prod response-inhibition induced by a composition of this invention in comparison with that of a standard antianxiety composition employing a compound such as diazepam as a measure of antiaggressive potential, and to obtain an indication of the duration of action of the compound.
  • compositions or appropriate vehicle are administered orally or
  • Aggressiveness and motor impairment are graded by response to a pole being introduced into the cage as described in Table II.
  • the individuals responsible for grading the responses are unaware of the dose levels received by the monkeys.
  • the study is designed as a double-blind, parallel, placebo-controlled multicenter trial.
  • the patients are randomized into four groups, placebo and 25, 50, and 75 mg tid of test composition.
  • the dosages are administered orally with food.
  • Patients are observed at four visits to provide baseline measurements. Visits 5-33 served as the treatment phase for the study.
  • any synergistic combination therapy greatly increases the therapeutic index of a composition in treating these psychiatric disorders.
  • a markedly decreased amount of a serotonin agonist may now be administered to a patient, presumably greatly lessening the likelihood and severity of any adverse events.
  • Rapid onset formulations such as buccal or sublingual may now be developed.
  • Sustained release formulations are now more feasible due to the lower amounts of active ingredient necessary .
  • compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal .
  • Many of the compounds employed in the methods of this invention are ef fective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a
  • the excipient when it serves as a diluent, it can be a solid,
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions,
  • emulsions emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is
  • the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, macrocrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include:
  • compositions of the invention can be any suitable lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propylhydroxybenzoates
  • sweetening agents and flavoring agents.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compounds are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 30 mg/kg of body weight.
  • range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especially preferred.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed
  • Capsules each containing 40 mg of medicament are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the
  • Capsules each containing 15 mg of medicament, are made as follows:
  • the active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain
  • hydrophilic drugs into lipid-soluble drugs or prodrugs are hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the
  • the administration of the serotonin agonist may be simultaneous with, before, or after the administration of the tachykinin receptor antagonist. If it is desired to administer the serotonin agonist simultaneously with the tachykinin receptor antagonist, the two active ingredients may be combined into one pharmaceutical formulation or two formulations may be administered to the patient.
  • the patient to be benefited by practice of the present invention is a patient having one or more of the disorders discussed in detail below, or who is at a
  • a patient with a heightened risk of contracting one of the present disorders is a patient, in the present contemplation, who is more likely than is a normal person to fall victim to that disorder.
  • the patient may have suffered from the disorder in the past, and be at risk of a relapse, or may exhibit symptoms which demonstrate to the physician or psychiatrist that the patient is under an abnormal risk of developing the disorder in its full form.
  • the disorders which are treated or prevented in the practice of the present invention may be described as follows. bulimia nervosa
  • DSM American Psychiatric Association
  • DSM 307.51 Bulimia nervosa, DSM 307.51, is characterized by uncontrollable binge eating, followed by self-induced purging, usually vomiting. Its prevalence is as high as 1%-3% among adolescent and young adult females. The disorder is well characterized and recognized by the health professions. The essential features of it are binge eating and inappropriate compensatory methods to prevent weight gain. Further, individuals with the disorder are
  • Obsessive-compulsive disorder DSM 300.3, is characterized by recurrent obsessions or compulsions which are severe enough to be time consuming or cause distress or impairment of the patient's life. Obsessions are
  • inventions include the following: amphetamine dependence, DSM 304.40
  • DSM sedative, hypnotic or anxiolytic dependence
  • DSM 305.40 polysubstance dependence
  • Panic attack, panic disorder and agoraphobia categorized as DSM 300.01, 300.21 and 300.22, affect between 1.5% and 3.5% of the population.
  • the disorders are characterized by irrational sense of imminent danger or doom, an urge to escape, or a fear of being in a situation from which escape might be difficult.
  • the patient exhibits symptoms such as palpitations, accelerated heart rate, sweating, sensations of shortness of breath, chest pain, nausea, dizziness, fear of dying, and the like, and may have such attacks very frequently.
  • Post-traumatic stress disorder afflicts patients following exposure to a traumatic stress involving personal experience of an event involving actual or threatened death of injury.
  • traumatic events include experiences such as military combat, personal assault, kidnapping, terrorist attack, torture, natural or man-made disasters, severe accidents, or being diagnosed with a dreaded illness. Learning about such events occurring to others, particularly a family member or close friend, also may produce the disorder. Triggering events which symbolize the traumatic event, such as an
  • DSM 290.11, 290.12, 290.13, 290.10, 290.3, 290.20, 290.21 and 290.0 affects between 2% and 4% of the population over 65 years old. The prevalence increases with age, particularly after 75 years of age, and is associated with Alzheimer's
  • Attention deficit hyperactivity disorder DSM 314.01 and 314.00
  • DSM 314.01 and 314.00 Attention deficit hyperactivity disorder
  • DSM 314.01 and 314.00 is primarily recognized as a disorder of children, but may well be found in adults as well. It is characterized by symptoms such as lack of attention, impulsivity, and excessive activity, resulting in high expenditure of effort accompanied with a low degree of accomplishment. Patients have difficulty or find it impossible to give attention to details, cannot sustain attention in tasks or even play, and make careless
  • Disruptive behavior disorder is a condition characterized by aggressive, destructive, deceitful and defiant activity.
  • Intermittent explosive disorder DSM 312.34, is characterized by episodes of failure to resist aggressive impulses, resulting in assault or destruction of property. The degree of aggressiveness expressed during episodes of this disorder is grossly disproportionate to any
  • the Southeastern Asian condition of amok is an episode of this disorder, cases of which have been reported in Canada and the United States as well .
  • Borderline personality disorder DSM 301.83, is marked by a pervasive pattern of instability of
  • Depression and behavioral problems associated with head injury, mental retardation or stroke are treated in the exercise of the present invention. Such depression and behavioral problems are distinct from the usual such disorders, because of their origin. Depression, of course, of the general type is quite prevalent and is now well-known, being well treated with pharmaceuticals such as, for example, fluoxetine.
  • Chronic fatigue syndrome is a condition which has been variously described and diagnosed. It is sometimes categorized as a low-grade viral infection, particularly caused by the Epstein-Barr virus. Since that virus is very widely found in the population, however, the diagnosis is problematic.
  • An alternative characterization of chronic fatigue syndrome is a physical-psychological disorder of the depression type, characterized primarily by lack of energy and listlessness .
  • Premenstrual dysphoric disorder is characterized by symptoms such as feelings of sadness, hopelessness or self-deprecation; anxiety or tenseness; tearfulness and lability of mood; persistent irritability and anger;
  • the disorder markedly interferes with the patient's life in all respects during the attack of the disorder.
  • the prevalence of the disorder in its most profound form has been estimated at 3%-5%, but there has been little systematic study on the course and stability of the condition.

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Abstract

Cette invention concerne des procédés de traitement ou de prévention de troubles psychiatriques, lesquels procédés consistent à administrer à un mammifère qui en a besoin, une combinaison se composant, d'une part, d'un antagoniste de récepteur de tachykinine et, d'autre part, soit d'un antagoniste de sérotonine, soit d'un inhibiteur sélectif de réabsorption de sérotonine. Cette administration peut être effectuée de manière concomitante ou régulière, l'un ou l'autre des deux éléments pouvant être administré en premier. Les troubles psychiatriques qu'il est possible de traiter par les procédés décrits dans la présente invention comprennent: les troubles de panique, les crises de panique, la dépression, l'anxiété, les troubles liés à la névrose obsessionnelle, les troubles liés au stress post-traumatique, les états limites de troubles de la personnalité, l'agoraphobie, les troubles d'hyperactivité du déficit de l'attention, les troubles de comportement perturbateur, les troubles explosifs intermittents, et les états limites de troubles de la personnalité.
PCT/US1996/001737 1995-02-10 1996-02-08 Procede de traitement ou de prevention de troubles psychiatriques WO1996024353A1 (fr)

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WO1997023455A1 (fr) * 1995-12-21 1997-07-03 Eli Lilly And Company Procedes de preparation d'antagonistes de recepteur de tachykinine non peptidyle
WO1997045119A1 (fr) * 1996-05-24 1997-12-04 Novartis Ag Utilisation d'antagonistes de la substance p pour traiter la phobie sociale
WO1998015277A2 (fr) * 1996-10-07 1998-04-16 Merck Sharp & Dohme Limited Antagoniste du recepteur nk-1 utilise comme antidepresseur et/ou agent anxiolytique
WO1998047514A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 et d'un inhibiteur selectif de reabsorption de la serotonine (ssri) dans le traitement de l'obesite
WO1998047513A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation des antagonistes du recepteur de nk-1 dans le traitement des troubles alimentaires
WO1999002163A1 (fr) * 1997-07-10 1999-01-21 Eli Lilly And Company Inhibiteurs de la production d'oxydant induite par des neutrophiles
WO1999007374A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes de recepteur de nk-1 dans le traitement du comportement agressif
WO1999007375A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement de troubles du comportement agressifs
WO1999007376A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement d'une manie
WO1999007373A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes de recepteur de nk-1 pour le traitement de la manie
US5919781A (en) * 1996-12-02 1999-07-06 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antogonists for treating substance use disorders
US5925627A (en) * 1996-12-02 1999-07-20 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating movement disorders
US5929054A (en) * 1996-12-02 1999-07-27 Merck Sharp Use of NK-1 receptor antagonists for treating sexual dysfunctions
US5952315A (en) * 1996-12-02 1999-09-14 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating bipolar disorders
US5977104A (en) * 1996-12-02 1999-11-02 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating bipolar disorders
WO1999064009A1 (fr) * 1998-06-11 1999-12-16 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles cognitifs
US6087348A (en) * 1997-12-01 2000-07-11 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating stress disorders
EP1017395A1 (fr) * 1997-08-28 2000-07-12 Merck & Co., Inc. Procede permettant de traiter le syndrome premenstruel ou le syndrome de la phase luteale tardive
US6096729A (en) * 1996-12-02 2000-08-01 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating amnestic disorders
US6100256A (en) * 1996-12-02 2000-08-08 Merck Sharp & Dohme Ltd. Use of NK-1 receptors antagonists for treating schizophrenic disorders
US6117855A (en) * 1996-10-07 2000-09-12 Merck Sharp & Dohme Ltd. Use of a NK-1 receptor antagonist and an antidepressant and/or an anti-anxiety agent
US6156749A (en) * 1997-12-01 2000-12-05 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating movement disorders
EP1099446A2 (fr) * 1999-11-10 2001-05-16 Pfizer Products Inc. Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste du récepteur NK-1 et un agent antidépressant ou anxiolitique
US6271230B1 (en) 1997-12-01 2001-08-07 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating cognitive disorders
WO2001095904A1 (fr) * 2000-06-12 2001-12-20 University Of Rochester Methode de traitement de symptomes de la variation hormonale, tels que les bouffees de chaleur, au moyen d'un antagoniste du recepteur de la tachykinine
JP2003520232A (ja) * 2000-01-18 2003-07-02 エフ．ホフマン−ラ ロシュ アーゲー 脳、脊髄および神経損傷の治療
US6613765B1 (en) 1996-12-02 2003-09-02 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating major depressive disorders
EP1440690A2 (fr) * 1999-07-08 2004-07-28 H.Lundbeck A/S Traitement des troules neurotiques
EP1556054A1 (fr) * 2002-05-29 2005-07-27 The Regents Of The University Of California Antagonisation de recepteurs nk-1 inhibant la toxicomanie
WO2008017753A2 (fr) * 2006-07-31 2008-02-14 Sanofi Aventis Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
FR2912057A1 (fr) * 2007-02-07 2008-08-08 Sanofi Aventis Sa Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
GB2448807A (en) * 2007-04-27 2008-10-29 Merck Sharp & Dohme Substituted fused benzene and pyridine derivatives useful as ligands for GABAA receptors
US7713984B2 (en) 1998-08-25 2010-05-11 Novartis Ag Pharmaceutical uses
US7718705B1 (en) 1999-09-03 2010-05-18 Eli Lilly And Company Methods of using rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfunction
US8969355B2 (en) 2006-06-16 2015-03-03 H. Lundbeck A/S 1-[2-(2,4 dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1a activity for the treatment of cognitive impairment
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023455A1 (fr) * 1995-12-21 1997-07-03 Eli Lilly And Company Procedes de preparation d'antagonistes de recepteur de tachykinine non peptidyle
WO1997045119A1 (fr) * 1996-05-24 1997-12-04 Novartis Ag Utilisation d'antagonistes de la substance p pour traiter la phobie sociale
AU726745B2 (en) * 1996-10-07 2000-11-16 Merck Sharp & Dohme Limited CNS-penetrant NK-1 receptor antagonists as antidepressant and/or an anti-anxiety agent
US6117855A (en) * 1996-10-07 2000-09-12 Merck Sharp & Dohme Ltd. Use of a NK-1 receptor antagonist and an antidepressant and/or an anti-anxiety agent
US6649614B2 (en) 1996-10-07 2003-11-18 Merck Sharp & Dohme Ltd. Use of a NK-1 receptor antagonist and an antidepressant and/or an anti-anxiety agent for treatment of depression or anxiety
WO1998015277A3 (fr) * 1996-10-07 1998-05-22 Merck Sharp & Dohme Antagoniste du recepteur nk-1 utilise comme antidepresseur et/ou agent anxiolytique
WO1998015277A2 (fr) * 1996-10-07 1998-04-16 Merck Sharp & Dohme Limited Antagoniste du recepteur nk-1 utilise comme antidepresseur et/ou agent anxiolytique
US6319953B1 (en) 1996-10-07 2001-11-20 Merck Sharp & Dohme Ltd. Treatment of depression and anxiety with fluoxetine and an NK-1 receptor antagonist
US5977104A (en) * 1996-12-02 1999-11-02 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating bipolar disorders
US6613765B1 (en) 1996-12-02 2003-09-02 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating major depressive disorders
US6100256A (en) * 1996-12-02 2000-08-08 Merck Sharp & Dohme Ltd. Use of NK-1 receptors antagonists for treating schizophrenic disorders
US5919781A (en) * 1996-12-02 1999-07-06 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antogonists for treating substance use disorders
US5925627A (en) * 1996-12-02 1999-07-20 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating movement disorders
US5929054A (en) * 1996-12-02 1999-07-27 Merck Sharp Use of NK-1 receptor antagonists for treating sexual dysfunctions
US6096729A (en) * 1996-12-02 2000-08-01 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating amnestic disorders
US5952315A (en) * 1996-12-02 1999-09-14 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating bipolar disorders
AU744261B2 (en) * 1997-04-24 2002-02-21 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating eating disorders
WO1998047513A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation des antagonistes du recepteur de nk-1 dans le traitement des troubles alimentaires
AU735760B2 (en) * 1997-04-24 2001-07-12 Merck Sharp & Dohme Limited Use of a NK-1 receptor antagonist and an SSRI for treating obesity
WO1998047514A1 (fr) * 1997-04-24 1998-10-29 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 et d'un inhibiteur selectif de reabsorption de la serotonine (ssri) dans le traitement de l'obesite
US6162805A (en) * 1997-04-24 2000-12-19 Merck Sharp & Dohme Limited Use of an NK-1 receptor antagonist and an SSRI for treating obesity
US6303610B1 (en) 1997-07-10 2001-10-16 Eli Lilly And Company Method of treating gout with certain indole compounds
WO1999002163A1 (fr) * 1997-07-10 1999-01-21 Eli Lilly And Company Inhibiteurs de la production d'oxydant induite par des neutrophiles
US6090819A (en) * 1997-08-04 2000-07-18 Merck Sharp & Dohme, Ltd. Use of NK-1 receptor antagonists for treating mania
WO1999007375A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement de troubles du comportement agressifs
WO1999007376A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement d'une manie
WO1999007373A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes de recepteur de nk-1 pour le traitement de la manie
US5952330A (en) * 1997-08-04 1999-09-14 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating mania
WO1999007374A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes de recepteur de nk-1 dans le traitement du comportement agressif
EP1017395A1 (fr) * 1997-08-28 2000-07-12 Merck & Co., Inc. Procede permettant de traiter le syndrome premenstruel ou le syndrome de la phase luteale tardive
EP1017395A4 (fr) * 1997-08-28 2003-06-04 Merck & Co Inc Procede permettant de traiter le syndrome premenstruel ou le syndrome de la phase luteale tardive
US6156749A (en) * 1997-12-01 2000-12-05 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating movement disorders
US6271230B1 (en) 1997-12-01 2001-08-07 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating cognitive disorders
US6087348A (en) * 1997-12-01 2000-07-11 Merck Sharp & Dohme Ltd. Use of NK-1 receptor antagonists for treating stress disorders
WO1999064009A1 (fr) * 1998-06-11 1999-12-16 Merck Sharp & Dohme Limited Utilisation d'un antagoniste du recepteur nk-1 dans le traitement des troubles cognitifs
US7713984B2 (en) 1998-08-25 2010-05-11 Novartis Ag Pharmaceutical uses
EP1440690A3 (fr) * 1999-07-08 2004-08-18 H.Lundbeck A/S Traitement des troules neurotiques
EP1440690A2 (fr) * 1999-07-08 2004-07-28 H.Lundbeck A/S Traitement des troules neurotiques
EP1440691A2 (fr) * 1999-07-08 2004-07-28 H.Lundbeck A/S Traitement des troubles neurotiques
EP1440691A3 (fr) * 1999-07-08 2004-08-25 H.Lundbeck A/S Traitement des troubles neurotiques
US6960613B2 (en) 1999-07-08 2005-11-01 H. Lundbeck A/S Treatment of neurotic disorders
US7265151B2 (en) 1999-07-08 2007-09-04 H. Lundbeck A/S Treatment of neurotic disorders
US7271194B2 (en) 1999-07-08 2007-09-18 H. Lundbeck A/S Treatment of neurotic disorders
US7718705B1 (en) 1999-09-03 2010-05-18 Eli Lilly And Company Methods of using rapid-onset selective serotonin reuptake inhibitors for treating sexual dysfunction
EP1099446A3 (fr) * 1999-11-10 2003-03-26 Pfizer Products Inc. Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste du récepteur NK-1 et un agent antidépressant ou anxiolitique
EP1099446A2 (fr) * 1999-11-10 2001-05-16 Pfizer Products Inc. Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste du récepteur NK-1 et un agent antidépressant ou anxiolitique
JP4794794B2 (ja) * 2000-01-18 2011-10-19 エフ．ホフマン−ラ ロシュ アーゲー 脳、脊髄および神経損傷の治療
JP2003520232A (ja) * 2000-01-18 2003-07-02 エフ．ホフマン−ラ ロシュ アーゲー 脳、脊髄および神経損傷の治療
WO2001095904A1 (fr) * 2000-06-12 2001-12-20 University Of Rochester Methode de traitement de symptomes de la variation hormonale, tels que les bouffees de chaleur, au moyen d'un antagoniste du recepteur de la tachykinine
EP1556054A1 (fr) * 2002-05-29 2005-07-27 The Regents Of The University Of California Antagonisation de recepteurs nk-1 inhibant la toxicomanie
EP1556054A4 (fr) * 2002-05-29 2007-09-05 Univ California Antagonisation de recepteurs nk-1 inhibant la toxicomanie
US9125909B2 (en) 2006-06-16 2015-09-08 H. Lundbeck A/S 1-[2-(2,4 dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment
US9227946B2 (en) 2006-06-16 2016-01-05 H. Lundbeck A/S 1-[2-(2,4 dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1a activity for the treatment of cognitive impairment
US11458134B2 (en) 2006-06-16 2022-10-04 H. Lundbeck A/S 1-[2-(2,4-dimeihylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment
US9861630B1 (en) 2006-06-16 2018-01-09 H. Lundbeck A/S 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment
US8969355B2 (en) 2006-06-16 2015-03-03 H. Lundbeck A/S 1-[2-(2,4 dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1a activity for the treatment of cognitive impairment
US9095588B2 (en) 2006-06-16 2015-08-04 H. Lundbeck A/S Process for preparing 1-[2-(2,4-dimethylphenysulfanyl)-pheny]piperazine or pharmaceutically acceptable salt thereof
US9101626B2 (en) 2006-06-16 2015-08-11 H. Lundbeck A/S Process for preparing 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salt thereof
US9125910B2 (en) 2006-06-16 2015-09-08 H. Lundbeck A/S 1-[2-(2,4 dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment
US9125908B2 (en) 2006-06-16 2015-09-08 H. Lundbeck A/S 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment
WO2008017753A2 (fr) * 2006-07-31 2008-02-14 Sanofi Aventis Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
WO2008017753A3 (fr) * 2006-07-31 2009-02-19 Sanofi Aventis Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
FR2912057A1 (fr) * 2007-02-07 2008-08-08 Sanofi Aventis Sa Composition pharmaceutique contenant en association le saredutant et un inhibiteur selectif de la recapture de la serotonine ou un inhibiteur de la recapture de la serotonine/norepinephrine
GB2448807A (en) * 2007-04-27 2008-10-29 Merck Sharp & Dohme Substituted fused benzene and pyridine derivatives useful as ligands for GABAA receptors
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (fr) 2012-11-14 2020-02-19 The Johns Hopkins University Procédés et compositions de traitement de la schizophrénie
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia

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